Myocardial stress and autophagy: mechanisms and potential therapies

Abstract

Autophagy is a ubiquitous cellular catabolic process responsive to energy stress status. Research over the last decade has revealed that cardiomyocyte autophagy is a prominent homeostatic pathway, important in adaptation to altered myocardial metabolic demand. The cellular machinery of autophagy involves targeted direction of macromolecules and organelles for lysosomal degradation. Autophagy activation has been identified as cardio-protective in some settings (i.e. ischemia and ischemic preconditioning). In other situations chronically elevated levels of autophagy have been linked with cardiopathology (i.e. sustained pressure overload and failure). Autophagy perturbation in diabetic cardiomyopathy is also observed – and has been associated with both adaptive and maladaptive stress responses. Recent findings indicate that various forms of selective autophagy operate in parallel to manage different catabolic ‘cargo’ types including mitochondria, large proteins, glycogen and lipid stores. In this Review, specific circumstances of autophagy induction associated with cardiac benefit or detriment are considered. The various static and dynamic approaches used for measurement of autophagy are critiqued and current inconsistencies in the understanding of autophagy regulation in the heart are highlighted. The future prospects for pharmacological intervention to achieve therapeutic manipulation of autophagic processes are canvassed.

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation

“…Although there is only a trend towards an increase in HSPA5 expression in patients with AF, diminished protein synthesis or enhanced degradation, by either the proteasome or autophagy, or exhaustion of the protein levels may be the underlying cause . There is ongoing debate about whether autophagy plays a beneficial or detrimental role in cardiac diseases . Excessive autophagy contributed to age‐related cardiac disease development, including heart failure, hypertension‐induced cardiac diseases, mitral regurgitation, and diabetic cardiomyopathy .…”

“…53 There is ongoing debate about whether autophagy plays a beneficial or detrimental role in cardiac diseases. 54,55 Excessive autophagy contributed to age-related cardiac disease development, including heart failure, hypertension-induced cardiac diseases, mitral regurgitation, and diabetic cardiomyopathy. 16,19,[56][57][58] Interestingly, all these cardiac diseases are recognized to represent a substrate for AF, 59 suggesting a role for autophagic activation in AF development.…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…For example, during starvation or in conditions of end-stage heart failure, the myocardium turns to metabolism of ketone bodies (16, 22). Furthermore, the activation of compensatory, evolutionarily conserved pathways such as autophagy and mitophagy may prevent deleterious changes in the cardiac myocytes, as well as the onset of cardiac dysfunction (50). …”

Fangchinoline Induces Apoptosis, Autophagy and Energetic Impairment in Bladder Cancer

“…However, our data indicated that the activation of autophagy in bladder cancer induced by Fcn was an adaptive response, whereas the blockade of autophagy enhanced Fcn-induced cell death. The appropriate activation of autophagy always plays a protective role in response to harmful irritation, such as stress injury and energy depletion [23,[25][26][27]. The activation of autophagy could sequester protein aggresomes and injured organelles to limit the injury [28,29].…”